Intramolecular 1,3-dipolar cycloaddition-mediated stereoselective synthesis of disubstituted cyclopentane: A simple model for the cyclopentane ring system of polycyclic oroidine alkaloids

Article abstract of DOI:10.1002/asia.201200820

We present a diastereoselective synthesis of disubstituted cyclopentane 8 having a nitrogen-containing quaternary carbon center, which is found in axinellamine A (5) and related compounds. During this work, we found that the 1,3-dipolar cycloaddition product 24 immediately underwent intramolecular redox reaction at the newly formed morpholin-2-one moiety, thus affording disubstituted cyclopentane containing a tertiary amine (9) stereoselectively in good yield. The amine 9 was successfully converted into guanidine 31, which corresponds to 8, through iminium cation-enamine isomerization. Copyright

Full text of DOI:10.1002/asia.201200820

FULL PAPER
DOI: 10.1002/asia.201200820
Intramolecular 1,3-Dipolar Cycloaddition-Mediated Stereoselective Synthesis
of Disubstituted Cyclopentane: A Simple Model for the Cyclopentane Ring
System of Polycyclic Oroidine Alkaloids
Yusuke Fukahori, Yohei Takayama, Takuya Imaoka, Osamu Iwamoto, and
Kazuo Nagasawa*[a]
Abstract: We present a diastereoselec-
tive synthesis of disubstituted cyclopen-
tane 8 having a nitrogen-containing
quaternary carbon center, which is
found in axinellamine A (5) and relat-
ed compounds. During this work, we
found that the 1,3-dipolar cycloaddition
product 24 immediately underwent in-
tramolecular redox reaction at the
newly formed morpholin-2-one moiety,
thus affording disubstituted cyclopen-
tane containing a tertiary amine (9)
stereoselectively in good yield. The
amine
9 was successfully converted
into guanidine 31, which corresponds
to 8, through iminium cation–enamine
isomerization.
Keywords: axinellamine · cycload-
dition · guanidine · oroidine · redox
chemistry
Introduction
Alkaloids of the oroidine class are natural products isolated
from marine sponges, mainly from Agelasidae, Axinellidae,
Dyctionellidae, and Hymeniacidonidae.[1] This alkaloid
family is structurally diverse as a consequence of metabolic
transformations of oroidin (1), which contains pyrrole and
imidazole groups; thus, the alkaloids are usually classified
according to the number of oroidine-related fragments.[1a]
Agelastatins 2 and 3, and (+)-dibromophakellin (4) are typi-
cal monomeric oroidine alkaloids, while axinellamine A (5),
massadine (6), and palau’amine (7) are classified as dimeric
congeners.[2,3] Since these alkaloids contain a characteristic
complex polycyclic ring system with contiguous asymmetric
stereocenters (Figure 1), they have attracted the attention of
synthetic chemists, and various synthetic approaches have
been reported.[4,5]
In our work on this class of alkaloids,[4i,j] we became inter-
ested in the dimeric compounds 5–7. These alkaloids com-
monly possess a synthetically challenging fully substituted
pentacyclic ring with a spiro-fused system.[6] As the entry
point for our synthetic studies of these alkaloids, we chose
the disubstituted cyclopentane 8, which contains two contig-
uous stereogenic centers corresponding to C11 and C16 of
the alkaloids, as a simple model for the pentacyclic ring
[a] Y. Fukahori, Y. Takayama, T. Imaoka, Dr. O. Iwamoto,
Prof. Dr. K. Nagasawa
Figure 1. Structures of oroidin (1) and representative monomeric and di-
meric analogs.
Department of Biotechnology and Life Science
Tokyo University of Agriculture and Technology
2-24-16 Naka-cho, Koganei, Tokyo 184-8588 (Japan)
Fax : (+81)42-388-7295
system. Herein, we describe the development of a diastereo-
selective synthesis of the disubstituted cyclopentane skele-
ton of 8, which incorporates the nitrogen-containing quater-
E-mail: knaga@cc.tuat.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201200820.
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Kazuo Nagasawa et al.
nary carbon centers of dimeric oroidin alkaloids, especially
those related to axinellamine A (5). The key reaction
proved to be an intramolecular 1,3-dipolar cycloaddition
(1,3-DC), followed immediately by intramolecular redox
transformation of the generated morpholin-2-one moiety of
the product.
Our synthetic plan for disubstituted cyclopentane 8 is de-
picted in Scheme 1. In this synthesis, we planned to con-
struct the quaternary carbon center at C16 by intramolecu-
lar 1,3-DC of 11, which contains a cyclic nitrone and unsatu-
rated ester.[7] During the reaction, the stereochemistry at
C11 was expected to be controlled. Reduction and degrada-
À
tion of the N O bond and morpholin-2-one moiety in 10
were expected to produce 8 via 9.
Scheme 2. Synthesis of isoxazolidine 10. Reagents and conditions:
a) (COCl)2, DMSO, CH2Cl2, À788C, 2 h, then Et3N, 5 min, À788C;
b) triethylphosphonoacetate, NaH, THF, 08C, 1 h; c) m-CPBA, CH2Cl2,
rt, 6 h, 92% (3 steps); d) trifluoromethanesulfonic acid, molecular sieve
4 ꢁ powder, DMSO, 1008C, 5.5 h, 71%; e) N,O-bisBoc-N-hydroxyglycine
(16), EDCI, DMAP, CH2Cl2, 08C, 0.5 h; f) TFA, CH2Cl2, rt, 6 h; g) tolu-
ene, MgSO4, K2CO3, 408C, 11 h, 33% (3 steps).
Scheme 1. Retrosynthetic analysis of disubstituted cyclopentane 8.
Results and Discussion
ly generated by TfOH.[8] The hydroxy group in 14 was acy-
lated with N,O-bisBoc-N-hydroxyglycine (16) in the pres-
ence of EDCI (1-ethyl-3-(3-dimethylaminopropyl) carbodii-
mide) to give 15, which was treated with TFA to give ni-
trone 11 by deprotection of the two Boc groups followed by
intramolecular cyclization of the resulting hydroxylamine
with ketone. The intramolecular 1,3-DC of 11 proceeded at
408C in toluene to give isoxazolidine 10 as a single diaste-
reomer in 33% yield from 14 (3 steps). The stereochemis-
tries in 10 were confirmed by means of nuclear Overhauser
effect (nOe) NMR studies, which showed that the desired
stereochemistries at C11 and C16 had been obtained.[9] In
this 1,3-DC reaction, two transition states, that is, the
pseudo-boat form (11-A) and the pseudo-chair form (11-B),
can be considered (Figure 2). Since the chair-form transition
state is more favorable, intramolecular 1,3-DC reaction pro-
ceeded exclusively from the transition state 11-B, thereby af-
fording the desired isomer 10.
Construction of the cyclopentane ring system 10 containing
consecutive stereogenic centers at C11 and C16 by means of
intramolecular 1,3-DC reaction is illustrated in Scheme 2.
Swern oxidation of the primary alcohol in 5-hexen-1-ol
(12) followed by Horner–Emmons reaction of the resulting
aldehyde generated the E-unsaturated ester, whose terminal
olefin was selectively oxidized with m-CPBA (m-chloroper-
benzoic acid) to give epoxide 13 in 92% yield (3 steps). The
epoxide 13 was then treated with DMSO in the presence of
a catalytic amount of TfOH (trifluoromethanesulfonic acid)
at 1008C, and a-hydroxyketone 14 was obtained in 71%
yield via the secondary carbocation, which was preferential-
Abstract in Japanese:
Figure 2. Transition state of the intramolecular 1,3-dipolar cycloaddition
(1,3-DC) of 11.
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À
With the isoxazolidine 10 in hand, reduction of the N O
bond (10 to 17) and removal of the morpholin-2-one moiety
(17 to 9) via 18 were examined (Scheme 3). First, hydroge-
Scheme 3. Synthesis of imine 18 from isoxazolidine 10. Reagents and
conditions: a) Pd(OH)2, H2, HCl aq./EtOH, rt, 2 h, 89%; b) m-CPBA,
CH2Cl2, rt, 1.5 h, 55%; c) PPh3, toluene, 1008C, 17 h, 66%.
Scheme 4. Synthesis of imine 25. Reagents and conditions: a) 21, EDCI,
DMAP, CH2Cl2, 08C, 1.5 h, 32%; b) TFA, CH2Cl2, rt, 1 h; c) 1,2-dichloro-
ethane, rt to 508C, 1.5 h, 74% (2 steps).
nolysis of 10 in the presence of a catalytic amount of Pd/C
or Pd(OH)2 in ethanol was examined for reduction of the
À
N O bond in 10. However, the reaction did not proceed
under these conditions, and only the starting compound 10
was recovered quantitatively. Addition of aqueous HCl was
effective in the presence of Pd(OH)2, and amine 17 was ob-
tained in 89% yield. However, the following oxidation of
the morpholin-2-one moiety to obtain imine 18 was prob-
lematic. We tried various oxidants, but the desired imine 18
was not formed, and only oxidation of the hydroxy group
proceeded. Thus, we explored an alternative approach for
conversion of 10 into 9. When m-CPBA oxidation was ap-
plied to isoxazolidine 10, nitrone 19 was obtained in 55%
yield.[10] This was reduced with triphenylphosphine to give
imine 18 in 66% yield.[11] Although imine 18, a precursor
for aminediol 9, was obtained from 10, the oxidation–reduc-
tion process was tedious. We envisaged that a more efficient
conversion of 10 might be achieved by installing a phenyl
group at the a-position of the morpholin-2-one moiety, since
the resulting benzylic position would be labile to reduction,
and aminediol 9 might be generated under simple reductive
conditions from the 1,3-DC adduct.
Thus, the ester 22 was synthesized by esterification of al-
cohol 14 with phenylglycine derivative (Æ)-21[12] in the pres-
ence of EDCI (Scheme 4). The ester 22, which was very
labile under basic conditions, was converted into nitrone 23
by deprotection of the TBDPS group with TFA, with simul-
taneous dehydrative cyclization of the resulting hydroxyla-
mine and ketone. The nitrone 23 was then subjected to 1,3-
DC reaction by heating at 508C in dichloroethane. To our
surprise, imine 25 was obtained stereoselectively in a single
step from 23 in 74% yield (2 steps from 22).[13] This result
can be explained in terms of an intramolecular redox reac-
tion; thus, enol formation of isoxazolidine 24 and subse-
Scheme 5. Proposed mechanism for the formation of imine 25 from iso-
xazolidine 24.
The cyclic imine 25 was further converted into bicyclic
ketone with guanidine 31 (Scheme 5). The cyclic imine 25
was hydrolyzed under acidic conditions with HCl to give
amine-diol 9 as a hydrochloric acid salt. Treatment of the
salt 9 with triethylamine in methanol concurrently generated
lactam 26, whose two hydroxy groups were acetylated with
acetic anhydride to give diacetate 27 in 82% yield from 25
(3 steps). After protection of the amino group with Boc
(95% yield), the resulting lactam 28 was reduced to aminal
29 with lithium borohydride in 71% yield. In this reaction,
the acetyl group on the secondary alcohol was deprotected
simultaneously. Subsequently, the Boc group was deprotect-
ed with TFA in dichloromethane to give ketone 30 through
an iminium cation–enamine isomerization.[14] Finally, guany-
lation was carried out with pseudothiourea 32[15] in the pres-
ence of silver (I) triflate and triethylamine, and guanidine 31
was obtained in 43% yield (2 steps). Compound 31 has a dis-
ubstituted cyclopentane skeleton with a nitrogen-containing
quaternary carbon center and can be regarded as a simple
model of the pentacyclic core structure of dimeric oroidin
alkaloids, especially those related to axinellamine A (5).
Scheme 6
Conclusions
À
quent N O bond cleavage with recovery of the keto-form
generated imine 25 (Scheme 5).
We achieved a diastereoselective synthesis of guanidine 31
with a disubstituted pentacyclic ring system. The contiguous
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and warmed to room temperature. The mixture was extracted twice with
CH2Cl2, and the combined organic layer was dried over MgSO4, filtered,
and concentrated to give crude aldehyde. To a solution of NaH (60%,
2.55 g, 63.7 mmol) in THF (240 mL) was added triethylphosphonoacetate
(10.2 mL, 51.0 mmol) at 08C under N2 atmosphere. After stirring for
5 min, crude aldehyde (25.5 mmol) in THF (15 mL) was added to the
above solution and the mixture was stirred for 1 h at 08C. The reaction
was quenched with aqueous sat. NH4Cl and extracted with ethyl acetate.
The combined organic layer was dried over MgSO4, filtered, and concen-
trated to give crude ester. To a solution of ether (4.24 g, 25.2 mmol) in
CH2Cl2 (200 mL) was added m-CPBA (11.4 g, 51.0 mmol) at 08C under
N2 atmosphere. After stirring for 6 h at room temperature, the reaction
was quenched with aqueous 10% Na2S2O3 and sat. NaHCO3, and extract-
ed with CH2Cl2. The organic layer was dried over MgSO4, filtered, and
concentrated in vacuo. The residue was purified by silica gel column
chromatography (n-hexane/ethyl acetate=8:1) to give epoxide 13 (4.31 g,
1
23.4 mmol, 92%). Spectral data for ester 13: H NMR (400 MHz, CDCl3)
d=6.93 (dt, J=6.9, 15.6 Hz, 1H), 5.84–5.80 (m, 1H), 4.17 (q, J=6.9 Hz,
2H) 2.92–2.88 (m, 1H), 2.74 (t, J=4.6 Hz, 1H), 2.46 (q, J=2.8 Hz, 1H),
2.26 (dq, J=1.4, 7.3 Hz, 2H), 1.72–1.46 (m, 4H), 1.27 ppm (t, J=7.3 Hz,
3H); 13C NMR (100 MHz, CDCl3) d=166.6, 148.3, 121.8, 60.2, 51.9, 46.9,
31.8, 31.7, 24.4, 14.2 ppm; HRMS (ESI, M+Na+) calcd for C10H16NaO3
207.0997, found 207.1005.
Scheme 6. Synthesis of guanidine 31. Reagents and conditions: a) HCl,
MeOH, 508C, 7 h; b) Et3N, MeOH, rt., 5 h; c) Ac2O, pyridine, rt, 5 h,
82% (3 steps); d) Boc2O, DMAP, Et3N, rt, 1 h, 95%; (e) LiBH4, THF, rt,
1 h, 71%; f) TFA, CH2Cl2, rt, 3 h; g) N-Boc-N’-Cbz-isothiopseudourea
(32), AgOTf, Et3N, DMF, rt, 1 h, 43% (2 steps).
a-Hydroxyketone 14: To a solution of epoxide 13 (4.31 g, 23.4 mmol) and
molecular sieve 4 ꢁ powder (4.68 g) in DMSO (50 mL) was added TfOH
(410 mL, 4.68 mmol) at room temperature under N2 atmosphere. After
stirring for 5.5 h at 1008C, the reaction was quenched with aqueous sat.
NaHCO3 and extracted with ethyl acetate. The organic layer was dried
over MgSO4, filtered, and concentrated in vacuo. The residue was puri-
fied by silica gel column chromatography (n-hexane/ethyl acetate=4:1)
to give a-hydroxyketone 14 (3.30 g, 16.5 mmol, 71%). Spectral data for
a-hydroxyl ketone 14: 1H NMR (400 MHz, CDCl3) d=6.85 (dt, J=6.9,
15.1 Hz, 1H), 5.80–5.76 (m, 1H), 4.18 (d, J=2.8 Hz, 1H), 4.13 (q, J=
7.8 Hz, 2H), 3.16 (br, 1H), 2.40 (t, J=7.3 Hz, 2H), 2.19 (q, J=7.3 Hz,
2H), 1.77 (quint, J=7.3 Hz, 2H), 1.23 ppm (t, J=7.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d=209.0, 166.3, 147.3, 122.2, 68.0, 60.2, 37.2, 31.1,
21.6, 14.1 ppm; HRMS (ESI, M+Na+) calcd for C10H16NaO4 223.0946,
found 223.0986.
stereogenic centers at C11 and C16 involving a nitrogen-
containing quaternary carbon center in 31 were selectively
constructed by intramolecular 1,3-DC reaction with cyclic
nitrone 11 or 23. In the case of 1,3-DC reaction with 23, in-
tramolecular redox reaction proceeded immediately follow-
ing the 1,3-DC reaction, effectively affording cyclic imine 25
in a single step in good yield. Further elaboration of 25 led
to the guanidine 31, which we regard as a simple model of
the pentacyclic ring system of dimeric oroidin alkaloids, es-
pecially those related to axinellamine A (5).
Carboxylic acid 16: To a solution of N,O-bis(tert-butoxycarbonyl)hydrox-
ylamine[16] (9.0 g, 38.61 mmol) in DMF (77 mL) was added NaH (60%,
1.55 g, 38.61 mmol), benzyl 2-bromoacetate (7.3 mL, 46.33 mmol), and
tetrabutylammonium iodide (713 mg, 1.93 mmol) at 08C under N2 atmos-
phere. After stirring for 5 h at room temperature, the reaction was
quenched with aqueous sat. NH4Cl and extracted with ethyl acetate. The
organic layer was dried over MgSO4, filtered, and concentrated to give
Experimental Section
crude benzyl ester (12.1 g). To
a solution of benzyl ester (408 mg,
1.07 mmol) in MeOH (17 mL) was added 10% Pd/C (40.8 mg), and the
reaction mixture was stirred at room temperature under an atmosphere
of hydrogen gas (balloon). After 2 h, ethyl acetate was added to the reac-
tion mixture. Subsequently, the mixture was filtered through a pad of
Celite and eluted with ethyl acetate. The filtrates were concentrated in
vacuo, and the residue was purified by silica gel column chromatography
(n-hexane/ethyl acetate=5:1) to give carboxylix acid 16 (307 mg,
1.06 mmol, 98%). Spectral data for carboxylic acid 16: 1H NMR
(300 MHz, CDCl3) d=4.36 (s, 2H), 1.53 (s, 9H), 1.49 ppm (s, 9H);
13C NMR (125 MHz, CDCl3) d=172.1, 154.6, 152.4, 85.7, 83.9, 52.0, 27.9,
27.6 ppm; HRMS (ESI, M+Na+) calcd for C12H21NNaO7 314.1216,
found 314.1204.
General
Flash chromatography was performed on Silica gel 60 (spherical, particle
size 40–100 mm; Kanto), Chromatorex NH (particle size 75–150 mm; Fuji
Silysia), or Florisil (particle size 75–150 mm; Wako). 1H and 13C NMR
spectra were recorded on JEOL JNM-AL 300, JNM-ECX 400, and JNM-
ECA 500 spectrometers. The spectra are referenced internally according
to residual solvent signals of CDCl3 (1H NMR; d=7.26 ppm, 13C NMR;
1
d=77.0 ppm). Data for H NMR were recorded as follows: chemical shift
(d, ppm), multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; quint,
quintet; m, multiplet; br, broad) integration, and coupling constant (Hz).
Data for 13C NMR are reported in terms of chemical shift (d, ppm). Mass
spectra were recorded on a JEOL JMS-T100 LC spectrometer in the
ESI-MS mode using methanol as a solvent.
Isoxazolidine 10: To
a solution of a-hydroxyketone 14 (458 mg,
2.29 mmol) in CH2Cl2 (20 mL) was added EDCI·HCl (1.07 g, 6.87 mmol),
carboxylic acid 16 (2.00 g, 6.87 mmol), and DMAP (84 mg, 0.69 mmol) at
08C under N2 atmosphere. After stirring for 30 min, the reaction was
quenched with phosphate buffer (pH 7.0) and extracted with CH2Cl2.
The organic layer was dried over MgSO4, filtered, and concentrated in
vacuo at below 258C to give ester 15 (650 mg). To a solution of crude
ester 15 (608 mg) in CH2Cl2 (20 mL) was added MgSO4 (2.0 g) and TFA
(4 mL) at 08C under N2 atmosphere. After stirring for 6 h at room tem-
perature, the reaction was diluted with CH2Cl2, filtered, and concentrated
Synthesis
Epoxide 13: To a solution of DMSO (9.1 mL, 127.4 mmol) in CH2Cl2
(200 mL) was added (COCl)2 (4.3 mL, 51.0 mmol) at À788C under N2 at-
mosphere. After stirring for 15 min, 5-hexen-1-ol (12) (3.0 mL,
25.5 mmol) was added to the above solution, and the mixture was stirred
for 2 h at À788C. Then Et3N (35.3 mL, 254.8 mmol) was added to the
mixture. After stirring for 5 min, the reaction was quenched with H2O
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Kazuo Nagasawa et al.
in vacuo at below 258C. The residue was dissolved in toluene (10 mL),
and K2CO3 (354 mg) and MgSO4 (2.0 g) were added at room temperature
under N2 atmosphere. After stirring for 11 h at 408C, the reaction was
quenched with aqueous sat. NaHCO3 and extracted with ethyl acetate.
The combined organic layer was dried over MgSO4, filtered, and concen-
trated in vacuo at below 258C. The residue was purified by silica gel
column chromatography (n-hexane/ethyl acetate=3:1) to give isoxazoli-
dine 10 (179 mg, 0.70 mmol, 2 steps 33%). Spectral data for isoxazolidine
128.5, 128.0, 127.5, 118.4, 69.3, 65.6, 27.2, 19.1 ppm; HRMS (ESI, M+
Na+) calcd for C27H31NNaO3Si 468.1971, found 468.1961.
To a solution of hydroxylamine (251 mg, 0.564 mmol) and [PdACHTUNGTRENNUNG(PPh3)4]
(13 mg, 0.011 mmol) in THF (5 mL) was added morpholine (98 mL,
1.13 mmol) at 08C under N2 atmosphere. After stirring for 30 min, the re-
action was quenched with H2O and extracted with ethyl acetate. The or-
ganic layer was dried over MgSO4, filtered, and concentrated in vacuo.
The residue was purified by silica gel column chromatography (n-hexane/
ethyl acetate=15:1 to 2:1) to give carboxylic acid 21 (138 mg,
0.341 mmol, 60%). Spectral data for carboxylic acid 21: 1H NMR
(400 MHz, CDCl3) d=7.77–7.08 (m, 15H), 4.65 (s, 1H), 4.47 (s, 1H),
1.09 ppm (s, 9H); 13C NMR (100 MHz, CDCl3) d=177.8, 136.0, 135.6,
133.2, 132.8, 129.8, 129.6, 128.7, 128.6, 128.0, 127.6, 69.2, 27.2, 19.1 ppm;
HRMS (ESI, M+Na+) calcd for C24H27NNaO3Si 428.1658, found
428.1647.
1
10: H NMR (400 MHz, CDCl3) d=4.34 (d, J=12.4 Hz, 1H), 4.23 (q, J=
7.3 Hz, 2H), 4.13 (d, J=12.4 Hz, 1H), 4.06 (d, J=8.7 Hz, 1H), 4.05 (d,
J=16.5 Hz, 1H), 3.81 (d, J=16.5 Hz, 1H), 2.99 (t, J=7.3 Hz, 1H), 1.96–
1.76 (m, 6H), 1.30 ppm (t, J=6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d=168.7, 168.3, 80.0, 73.4, 70.5, 61.7, 56.9, 52.8, 35.0, 30.1, 23.2, 14.1 ppm;
HRMS (ESI, M+Na+) calcd for C12H17NNaO5 278.1004, found 278.1010.
Nitrone 19: To a solution of isoxazolidine 10 (21 mg, 0.083 mmol) in
CH2Cl2 (1 mL) was added m-CPBA (28 mg, 0.124 mmol) at 08C under
N2 atmosphere. After stirring for 1.5 h at room temperature, the reaction
was quenched with aqueous 10% Na2S2O3 and sat. NaHCO3, and extract-
ed with CH2Cl2. The organic layer was dried over MgSO4, filtered, and
concentrated in vacuo. The residue was purified by silica gel column
chromatography (n-hexane/ethyl acetate=1:1) to give nitrone 19
(12.4 mg, 0.046 mmol, 55%). Spectral data for nitrone 19: 1H NMR
(400 MHz, CDCl3) d=7.16 (s, 1H), 4.79 (d, J=12.6 Hz, 1H), 4.47 (d, J=
9.2 Hz, 1H), 4.22 (q, J=7.5 Hz, 2H), 4.19 (d, J=12.0, 1H), 3.18 (br, 1H),
Ester 22: To a solution of a-hydroxyketone 14 (92 mg, 0.457 mmol), car-
boxylic acid 21 (371 mg, 0.915 mmol), and DMAP (11 mg, 0.091 mmol) in
CH2Cl2 (4 mL) was added EDCI·HCl (377 mg, 1.371 mmol) at 08C under
N2 atmosphere. After stirring for 1.5 h, the reaction was quenched with
H2O and extracted with CH2Cl2. The organic layer was dried over
MgSO4, filtered, and concentrated in vacuo. The residue was purified by
silica gel column chromatography (n-hexane/ethyl acetate=50:1 to 30:1)
to give ester 22 (86 mg, 0.146 mmol, 32%). Spectral data for ester 22:
1H NMR (400 MHz, CDCl3) d=7.79–7.11 (m, 15H), 6.88 (dt, J=6.4,
15.1 Hz, 1H), 6.02 (br, 1H), 5.81 (d, J=15.6 Hz, 1H), 4.72 (d, J=2.8 Hz,
2H), 4.60 (s, 1H), 4.20 (q, J=6.9 Hz, 2H), 2.40 (dq, J=3.7, 7.3 Hz, 2H),
2.14 (q, J=6.9 Hz, 2H), 1.73 (quint, J=7.3 Hz, 2H), 1.30 (t, J=7.3 Hz,
3H), 1.12 ppm (s, 9H); 13C NMR (100 MHz, CDCl3) d=203.3, 171.9,
166.4, 147.7, 135.9, 135.6, 133.3, 132.7, 129.8, 129.6, 128.7, 128.6, 128.0,
127.5, 122.0, 69.1, 68.4, 60.2, 37.6, 31.0, 27.2, 21.1, 19.1, 14.2 ppm; HRMS
(ESI, M+Na+) calcd for C34H41NNaO6Si 610.2601, found 610.2572.
2.41–2.35 (m, 1H), 2.16–2.10 (m, 2H), 2.06–1.94 (m, 2H), 1.92–1.86ACTHNUTRGENUG(N m,
1H), 1.65–1.57 (m, 1H), 1.29 ppm (t, 7.5 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d=173.7, 159.1, 126.1, 77.7, 71.6, 71.2, 62.0, 50.8, 36.3, 30.3, 24.0,
14.1 ppm; HRMS (ESI, M+Na+) calcd for C12H17NNaO6 294.0954,
found 294.0953.
Imine 18: To a solution of nitrone 19 (96 mg, 0.35 mmol) in toluene
(4 mL) was added PPh3 (372 mg, 1.42 mmol) at room temperature under
N2 atmosphere. After stirring for 17 h at 1008C, the reaction was concen-
trated in vacuo. The residue was purified by silica gel column chromatog-
raphy (n-hexane/ethyl acetate=3:1) to give imine 18 (60.3 mg,
0.235 mmol, 66%). Spectral data for imine 18: 1H NMR (400 MHz,
CDCl3) d=7.71 (s, 1H), 4.55 (d, J=11.5 Hz, 1H), 4.31 (dd, J=5.5,
7.3 Hz, 1H), 4.22 (q, J=7.3 Hz, 2H), 4.15 (d, J=11.5 Hz, 1H), 3.50 (d,
J=8.7 Hz, 1H), 2.15–1.54 (m, 6H) 1.29 ppm (t, J=7.3 Hz, 3H);
13C NMR (100 MHz, CDCl3) d=174.1, 154.8, 150.6, 72.5, 71.7, 66.8, 61.5,
48.3, 36.9, 28.7, 23.6, 14.2 ppm; HRMS (ESI, M+Na+) calcd for
C12H17NNaO5 278.1004, found 278.0969.
Imine 25: To a solution of ester 22 (86 mg, 0.146 mmol) in CH2Cl2 (1 mL)
was added TFA (0.5 mL) at room temperature under N2 atmosphere.
After stirring for 1 h, the reaction was concentrated in vacuo, and the res-
idue was dissolved in 1,2-dichloroethane (1.5 mL). The mixture was then
heated at 508C for 30 min, concentrated in vacuo, and the residue was
purified by silica gel column chromatography (n-hexane/ethyl acetate=
50:1 to 30:1) to give imine 25 (35.8 mg, 0.106 mmol, 74%). Spectral data
for imine 25: 1H NMR (300 MHz, CDCl3) d=7.94–7.91 (m, 2H), 7.52–
7.40 (m, 3H), 4.52 (d, J=11.4 Hz, 1H), 4.35 (q, J=4.5 Hz, 1H), 4.23 (d,
J=11.4 Hz, 1H), 4.02 (q, J=7.2 Hz, 2H), 2.36–2.29 (m, 1H), 2.26–2.17
(m, 2H), 2.05–1.93 (m, 2H), 1.75–1.60 (m, 2H), 1.05 ppm (t, J=7.2 Hz,
3H); 13C NMR (75 MHz, CDCl3) d=174.0, 156.2, 155.3, 133.4, 131.2,
128.6, 128.2, 72.1, 66.8, 61.2, 47.6, 35.9, 28.6, 23.6, 13.7 ppm; HRMS (ESI,
M+Na+) calcd for C18H21NNaO5 354.1317, found 354.1330.
Carboxylic acid 21: To
a
solution of (Æ)-mandelic acid (1.00 g,
6.57 mmol) and K2CO3 (2.72 g, 19.7 mmol) in DMF (40 mL) was added
allyl bromide (556 mL, 6.57 mmol) at room temperature under N2 atmos-
phere. After stirring for 5 h, the reaction was quenched with aqueous sat.
NH4Cl and extracted with ethyl acetate. The organic layer was dried over
MgSO4, filtered, and concentrated in vacuo. The residue was purified by
silica gel column chromatography (n-hexane/ethyl acetate=10:1 to 5:1)
to give the allyl ester (1.15 g, 5.98 mmol, 91%). Spectral data for the allyl
ester: 1H NMR (400 MHz, CDCl3) d=7.45–7.31 (m, 5H), 5.88–5.78 (m,
1H), 5.21–5.12 (m, 3H), 4.71–4.61 (m, 2H), 3.46 ppm (d, J=5.5 Hz, 1H);
13C NMR (75 MHz, CDCl3) d=173.3, 138.1, 131.0, 128.5, 128.4, 126.5,
118.7, 72.8, 66.4 ppm; HRMS (ESI, M+Na+) calcd for C11H12NaO3
215.0684, found 215.0699.
Lactam 27: To a solution of imine 25 (432 mg, 1.28 mmol) in methanol
(5 mL) was added HCl (1 mL) at room temperature. After stirring for
7 h at 508C, the reaction was concentrated in vacuo to give crude amine
9. To a solution of crude amine 9 in methanol (5 mL) was added Et3N
(1 mL) at room temperature. After stirring for 5 h at room temperature,
the reaction was concentrated in vacuo to give lactam 26. To a solution
of crude lactam 26 in Ac2O (7 mL) was added pyridine (7 mL) at room
temperature. After stirring for 5 h, the reaction was concentrated in
vacuo. The residue was purified by silica gel column chromatography (n-
hexane/ethyl acetate=1:1 to 1:5) to give lactam 27 (267 mg, 1.05 mmol,
82%, 3 steps). Spectral data for lactam 27: 1H NMR (300 MHz, CDCl3)
d=6.60–6.56 (br, 1H), 5.37 (d, J=8.9 Hz, 1H), 4.26 (d, J=11.4 Hz, 1H),
3.96 (d, J=11.4 Hz, 1H), 2.93–2.86 (m, 1H), 2.17 (s, 3H), 2.09 (s, 3H),
1.80–1.63 ppm (brm, 6H); 13C NMR (75 MHz, CDCl3) d=172.8, 170.6,
170.2, 71.7, 68.4, 67.6, 45.4, 36.8, 25.9, 24.6, 20.8, 20.6 ppm; HRMS (ESI,
M+Na+) calcd for C12H17NNaO5 278.1004, found 278.1004.
To a solution of allyl ester (28 mg, 0.143 mmol) and DIEA (98.5 mL,
0.572 mmol) in CH2Cl2 (1 mL) was added Tf2O (27 mL, 0.157 mmol) at
À788C under N2 atmosphere. After stirring for 15 min, NH2OTBDPS
(42 mg, 0.286 mmol) in CH2Cl2 (1 mL) was added to the above solution,
and the mixture was stirred at room temperature. After stirring for 2 h,
the reaction was quenched with aqueous sat. NaHCO3 at 08C. The mix-
ture was extracted with twice with CH2Cl2, and the combined organic
layer was dried over MgSO4, filtered, and concentrated in vacuo. The res-
idue was purified by silica gel column chromatography (n-hexane/ethyl
acetate=100:1 to 50:1) to give hydroxylamine (30.7 mg, 0.069 mmol,
48%). Spectral data for hydroxylamine: 1H NMR (400 MHz, CDCl3) d=
7.77–7.01 (m, 15H), 5.97–5.87 (m, 1H), 5.34–5.21 (m, 2H), 4.81–4.65 (m,
2H), 4.47 (s, 1H), 1.09 ppm (s, 9H); 13C NMR (100 MHz, CDCl3) d=
172.2, 136.0, 135.9, 135.8, 135.7, 133.5, 133.4, 133.2, 131.8, 129.7, 129.6,
Lactam 28: To a solution of lactam 27 (141 mg, 0.554 mmol), Et3N
(192 mL, 1.39 mmol), and DMAP (7 mg, 0.055 mmol) in CH2Cl2 (5 mL)
was added Boc2O (242 mg, 1.11 mmol) at room temperature under N2 at-
mosphere. After stirring for 1 h, the reaction was quenched with aqueous
sat. NH4Cl and extracted with CH2Cl2. The organic layer was dried over
MgSO4, filtered, and concentrated in vacuo. The residue was purified by
silica gel column chromatography (n-hexane/ethyl acetate=10:1 to 2:1)
Chem. Asian J. 2013, 8, 244 – 250
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Kazuo Nagasawa et al.
to give lactam 28 (187 mg, 0.526 mmol, 95%). Spectral data for lactam
28: 1H NMR (300 MHz, CDCl3) d=5.50 (d, J=9.3 Hz, 1H), 4.79 (d, J=
11.4 Hz, 1H), 3.97 (d, J=11.4 Hz, 1H), 2.82–2.73 (m, 1H), 2.16 (s, 3H),
2.08 (s, 3H), 2.07–1.97 (brm, 2H), 1.85–1.58 (brm, 4H), 1.53 ppm (s, 9H);
13C NMR (75 MHz, CDCl3) d=169.9, 169.7, 169.5, 148.8, 83.6, 71.2, 70.9,
66.5, 44.8, 37.0, 27.6, 26.6, 24.7, 20.4, 20.2 ppm; HRMS (ESI, M+Na+)
calcd for C17H25NNaO7 378.1529, found 378.1567.
Quinn, J. Org. Chem. 1999, 64, 731–735; d) R. B. Kinnel, H. P.
Gehrken, P. J. Scheuer, J. Am. Chem. Soc. 1993, 115, 3376–3377;
e) S. Nishimura, S. Matsunaga, M. Shibasaki, K. Suzuki, K. Furihata,
R. W. M. Van Soest, N. Fusetani, Org. Lett. 2003, 5, 2255–2257.
[3] The structure of palau’amine was revised, see: a) A. Grube, M.
Kçck, Angew. Chem. 2007, 119, 2372–2376; Angew. Chem. Int. Ed.
2007, 46, 2320–2324; b) H. Kobayashi, K. Kitamura, K. Nagai, Y.
Nakao, N. Fusetani, R. W. M. van Soest, S. Matsunaga, Tetrahedron
Lett. 2007, 48, 2127–2129; c) M. S. Buchanan, A. R. Carroll, R. J.
Quinn, Tetrahedron Lett. 2007, 48, 4573–4574.
[4] For representative total syntheses of monomeric oroidine alkaloids,
see:a) M. Movassaghi, D. S. Siegel, S. Han, Chem. Sci. 2010, 1, 561–
566; b) Y. Menjo, A. Hamajima, N. Sasaki, Y. Hamada, Org. Lett.
2011, 13, 5744–5747; c) J. C. P. Reyes, D. Romo, Angew. Chem.
2012, 124, 6976–6979; Angew. Chem. Int. Ed. 2012, 51, 6870–6873;
d) T. Kano, R. Sakamoto, M. Akakura, K. Maruoka, J. Am. Chem.
Soc. 2012, 134, 7516–7520. For reviews of other agelastatin synthe-
ses, see: e) G. Dong, Pure Appl. Chem. 2010, 82, 2231–2246;
f) L. H. Foley, G. Bꢂchi, J. Am. Chem. Soc. 1982, 104, 1776–1777;
g) K. J. Wiese, K. Yakushijin, D. A. Horne, Tetrahedron Lett. 2002,
43, 5135–5136; h) K. S. Feldman, A. P. Koumbourdis, M. Fodor, J.
Org. Chem. 2007, 72, 8076–8086; i) T. Imaoka, O. Iwamoto, K. No-
guchi, K. Nagasawa, Angew. Chem. 2009, 121, 3857–3859; Angew.
Chem. Int. Ed. 2009, 48, 3799–3801; j) T. Imaoka, T. Akimoto, O.
Iwamoto, K. Nagasawa, Chem. Asian J. 2010, 5, 1810–1816;
k) N. M. Hewlett, J. J. Tepe, Org. Lett. 2011, 13, 4550–4553. For
other total syntheses and/or synthetic studies of these alkaloids, see
also ref. [1].
[5] For total syntheses of axinellamines, massadines, and palau’amine,
see: a) J. Yamaguchi, I. B. Seiple, I. S. Young, D. P. OꢃMalley, M.
Maue, P. S. Baran, Angew. Chem. 2008, 120, 3634–3636; Angew.
Chem. Int. Ed. 2008, 47, 3578–3580; b) D. P. O’Malley, J. Yamagu-
chi, I. S. Young, I. B. Seiple, P. S. Baran, Angew. Chem. 2008, 120,
3637–3639; Angew. Chem. Int. Ed. 2008, 47, 3581–3583; c) S. Su,
I. B. Seiple, I. S. Young, P. S. Baran, J. Am. Chem. Soc. 2008, 130,
16490–16491; d) I. B. Seiple, S. Su, I. S. Young, C. A. Lewis, J. Ya-
maguchi, P. S. Baran, Angew. Chem. 2010, 122, 1113–1116; Angew.
Chem. Int. Ed. 2010, 49, 1095–1098; e) S. Su, R. A. Rodriguez, P. S.
Baran, J. Am. Chem. Soc. 2011, 133, 13922–13925; f) I. B. Seiple, S.
Su, I. S. Young, A. Nakamura, J. Yamaguchi, L. Jørgensen, R. A.
Rodriguez, D. P. OꢃMalley, T. Gaich, M. Kçck, P. S. Baran, J. Am.
Chem. Soc. 2011, 133, 14710–14726. For recent synthetic studies for
these alkaloids, see: g) S. G. Koenig, S. M. Miller, K. A. Leonard,
R. S. Lçwe, B. C. Chen, D. J. Austin, Org. Lett. 2003, 5, 2203–2206;
h) X. Tan, C. Chen, Angew. Chem. 2006, 118, 4451–4454; Angew.
Chem. Int. Ed. 2006, 45, 4345–4348; i) B. A. Lanman, L. E. Over-
man, R. Paulini, N. S. White, J. Am. Chem. Soc. 2007, 129, 12896–
12900; j) R. Sivappa, N. M. Hernandez, Y. He, C. J. Lovely, Org.
Lett. 2007, 9, 3861–3864; k) M. S. Bultman, J. Ma, D. Y. Gin,
Angew. Chem. 2008, 120, 6927–6930; Angew. Chem. Int. Ed. 2008,
47, 6821–6824; l) A. Breder, G. Chinigo, A. Waltman, E. M. Car-
reira, Angew. Chem. 2008, 120, 8642–8645; Angew. Chem. Int. Ed.
2008, 47, 8514–8517; m) M. A. Zancanella, D. Romo, Org. Lett.
2008, 10, 3685–3688; n) T. A. Cernak, J. L. Gleason, J. Org. Chem.
2008, 73, 102–110; o) K. Namba, Y. Kaihara, H. Yamamoto, H.
Imagawa, K. Tanino, R. M. Williams, M. Nishizawa, Chem. Eur. J.
2009, 15, 6560–6563; p) Q. Li, P. Hurley, H. Ding, A. G. Roberts, R.
Akella, P. G. Harran, J. Org. Chem. 2009, 74, 5909–5919; q) R. Si-
vappa, S. Mukherjee, H. V. R. Dias, C. J. Lovely, Org. Biomol.
Chem. 2009, 7, 3215–3218; r) K. Namba, M. Inai, U. Sundermeier,
T. J. Greshock, R. M. Williams, Tetrahedron Lett. 2010, 51, 6557–
6559; s) K. S. Feldman, A. Y. Nuriye, J. Li, J. Org. Chem. 2011, 76,
5042–5060; t) Z. Ma, J. Lu, X. Wang, C. Chen, Chem. Commun.
2011, 47, 427–429.
Aminal 29: To a solution of lactam 28 (335 mg, 0.944 mmol) in THF
(5 mL) was added LiBH4 in THF (630 mL, 1.89 mmol) at 08C under N2
atmosphere. After stirring for 1 h at room temperature, the reaction was
quenched with aqueous sat. NH4Cl and extracted with ethyl acetate. The
combined organic layer was dried over MgSO4, filtered, and concentrated
in vacuo. The residue was purified by silica gel column chromatography
(n-hexane/ethyl acetate=3:1 to 2:1) to give aminal 29 (210.3 mg,
0.667 mmol, 71%). Spectral data for aminal 29: 1H NMR (300 MHz,
CDCl3) d=5.41 (d, J=3.8 Hz, 1H), 5.03 (dd, J=4.1, 7.6 Hz, 1H), 4.73 (d,
11.4 Hz, 1H), 3.79 (d, J=11.0 Hz, 1H), 2.93 (q, J=7.6 Hz, 1H), 2.10 (s,
3H), 1.84–1.61 (m, 6H), 1.49 ppm (s, 9H); 13C NMR (100 MHz, CDCl3)
d=170.8, 154.7, 88.7, 81.3, 75.2, 73.3, 66.4, 49.4, 37.1, 28.4, 26.0, 25.4,
21.0 ppm; HRMS (ESI, M+Na+) calcd for C15H25NNaO6 338.1580,
found 338.1579.
Guanidine 31: To a solution of aminal 29 (11 mg, 0.035 mmol) in CH2Cl2
(5 mL) was added TFA (0.1 mL) at room temperature. After stirring for
3 h at room temperature, the reaction was concentrated in vacuo to give
crude amine 30. To a solution of crude amine 30 (0.035 mmol), Et3N
(9.7 mL, 0.071 mmol), and N-Boc-N’-Cbz-isothiopseudourea (32; 19 mg,
0.053 mmol) in DMF (0.3 mL) was added AgOTf (14 mg, 0.053 mmol) at
room temperature under N2 atmosphere. After stirring for 1 h, the reac-
tion mixture was diluted with ethyl acetate and filtered through a pad of
Celite. The filtrates were washed with H2O and brine. The organic layer
was dried over MgSO4, filtered, and concentrated in vacuo. The residue
was purified by Florisil column chromatography (n-hexane/ethyl ace-
tate=5:1 to 1:1) to give guanidine 31 (7.6 mg, 0.015 mmol, 43%). Spec-
1
tral data for guanidine 31: H NMR (300 MHz, CDCl3) d=9.99 (br, 1H),
7.41–7.30 (m, 5H), 5.30 (d, J=11.4 Hz, 1H), 5.14 (s, 2H), 5.12 (d, J=
9.6 Hz, 1H), 4.36 (d, J=19.3 Hz, 1H), 4.14 (d, J=18.2 Hz, 1H), 4.10 (d,
J=11.3 Hz, 1H), 2.87–2.70 (m, 1H), 2.02 (s, 3H), 1.97–1.68 (brm, 6H),
1.47 ppm (s, 9H); 13C NMR (100 MHz, CDCl3) d=210.3, 170.4, 162.2,
153.3, 150.3, 136.6, 128.6, 128.4, 128.1, 127.9, 127.9, 82.7, 67.4, 66.9, 57.0,
56.9, 35.2, 29.6, 28.2, 28.0, 25.8, 20.7 ppm; HRMS (ESI, M+Na+) calcd
for C24H31N3NaO6 469.2060, found 469.2049.
Acknowledgements
This work was financially supported in part by a Grant-in-Aid for chal-
lenging Exploratory Research and Grant-in Aid for Scientific Research
on Innovative Area. T.I. is grateful for financial support from the JSPS
Predoctoral Fellowships for Young Scientists.
[1] For reviews, see: a) A. Al Mourabit, P. Potier, Eur. J. Org. Chem.
2001, 237–243; b) H. Hoffmann, T. Lindel, Synthesis 2003, 1753–
1783; c) D. E. N. Jacquot, T. Lindel, Curr. Org. Chem. 2005, 9, 1551–
1565; d) M. Kçck, A. Grube, I. B. Seiple, P. S. Baran, Angew. Chem.
2007, 119, 6706–6714; Angew. Chem. Int. Ed. 2007, 46, 6586–6594;
e) S. M. Weinreb, Nat. Prod. Rep. 2007, 24, 931–948; f) H. D. Arndt,
M. Riedrich, Angew. Chem. 2008, 120, 4864–4867; Angew. Chem.
Int. Ed. 2008, 47, 4785–4788; g) B. Heasley, Eur. J. Org. Chem.
2009, 1477–1489; h) B. Forte, B. Malgesini, C. Piutti, F. Quartieri,
A. Scolaro, G. Papeo, Mar. Drugs 2009, 7, 705–753; i) A. Al-Moura-
bit, M. A. Zancanella, S. Tilvi, D. Romo, Nat. Prod. Rep. 2011, 28,
1229–1260.
[6] These alkaloids possess a range of interesting biological activities;
see ref. [1] and [2].
[7] For selected examples for the synthesis of polycyclic systems using
1,3-dipolar cycloaddition and nitrones, see: a) G. W. Gribble, T. C.
Barden, J. Org. Chem. 1985, 50, 5900–5902; b) G. M. Williams, S. D.
[2] For isolation of these alkaloids, see: a) M. D’Ambrosio, A. Guer-
riero, C. Debitus, O. Ribes, J. Pusset, S. Leroy, F. Pietra, J. Chem.
Soc. Chem. Commun. 1993, 1305–1306; b) P. R. Burkholder, G. M.
Sharma, Lloydia 1969, 32, 466–483; c) A. S. Urban, P. de Almeida
Leone, A. R. Carroll, G. A. Fechner, J. Smith, J. N. A. Hooper, R. J.
Chem. Asian J. 2013, 8, 244 – 250
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www.chemasianj.org
Kazuo Nagasawa et al.
Roughley, J. E. Davies, A. B. Holmes, J. Am. Chem. Soc. 1999, 121,
4900–4901; c) F. M. Cordero, M. Gensini, A. Goti, A. Brandi, Org
Lett. 2000, 2, 2475–2477; d) C.-H. Tan, A. B. Holmes, Chem. Eur. J.
2001, 7, 1845–1854; e) J. D. White, P. R. Blakemore, E. A. Korf,
A. F. T. Yokochi, Org. Lett. 2001, 3, 413–415; f) V. Nair, T. D. Suja,
Tetrahedron 2007, 63, 12247–12275; g) O. Iwamoto, H. Koshino, D.
Hashizume, K. Nagasawa, Angew. Chem. 2007, 119, 8779–8782;
Angew. Chem. Int. Ed. 2007, 46, 8625–8626; h) A. Brandi, F. Cardo-
na, S. Cicchi, F. M. Cordero, A. Goti, Chem. Eur. J. 2009, 15, 7808–
7821; i) T. Erhard, G. Ehrlich, P. Metz, Angew. Chem. 2011, 123,
3979–3981; Angew. Chem. Int. Ed. 2011, 50, 3892–3894; j) I. Delso,
T. Tejero, A. Goti, P. Merino, J. Org. Chem. 2011, 76, 4139–4143.
[8] a) M. A. Khuddus, D. Swern, J. Am. Chem. Soc. 1973, 95, 8393–
8402; b) B. M. Trost, M. J. Fray, Tetrahedron Lett. 1988, 29, 2163–
2166; c) T. Tsuji, Bull. Chem. Soc. Jpn. 1989, 62, 645–647.
[11] P. Cividino, M. D. Andries, J. Ou, S. Py, P. H. Toy, Tetrahedron Lett.
2009, 50, 7038–7042.
[12] The synthesis of (Æ)-21 was conducted using the method developed
by Ottenheijm and co-workers, see: R. W. Feenstra, E. H. M. Stok-
kingreef, H. C. J. Ottenheijm, Tetrahedron Lett. 1987, 28, 1215–1218.
We examined the synthesis of optically active form of 21; however,
a part of the product was epimerized, which was also mentioned in
the manuscript by Ottenheijm.
[13] Stereochemistries at C11 and C16 are controlled by the same transi-
tion state (see Scheme 2).
[14] The interesting isomerization to 30 was unexpected. Installation of
the guanidine group could be achieved only with 30, not 9 or 26 and
its derivatives.
[15] Y. Sawayama, T. Nishikawa, Angew. Chem. 2011, 123, 7314–7316;
Angew. Chem. Int. Ed. 2011, 50, 7176–7178.
[9] The stereochemistry at C10 was not determined from the NMR ex-
periments. It was speculated based on the olefin geometry in 13.
[10] a) S. A. Ali, M. I. M. Wazeer, Tetrahedron 1993, 49, 4339–4354;
b) T. Ishiwata, T. Hino, H. Koshino, Y. Hashimoto, T. Nakata, K.
Nagasawa, Org. Lett. 2002, 4, 2921–2924.
[16] M. A. Staszak, C. W. Doecke, Tetrahedron Lett. 1993, 34, 7043–
7044.
Received: September 3, 2012
Published online: October 18, 2012
Chem. Asian J. 2013, 8, 244 – 250
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